Physostigmine, represented by the formula I below, ##STR3## is a naturally-occurring, optically-active compound which has shown encouraging responses in treating Alzheimer's disease, due to its anticholinesterase activity. However, as in the case of many pharmaceuticals, one of the enantiomers of this compound i.e., the (3aS) enantiomer, demonstrates significantly greater efficacy as compared to the other.
The (3aS) enantiomer of physostigmine is presently extracted from Calabar beans, which are of West African origin. However, the limited availability of these beans has resulted in a scarcity of physostigmine, and what little is available is relatively expensive. These factors have caused the pharmaceutical industry and academia to devise alternate routes to synthetically obtain the (3aS) enantiomer of physostigmine.
In order to synthesize the (3aS) enantiomer of physostigmine, it is necessary to provide an optically-pure intermediate, (3aS-cis)-esermethole (II). ##STR4## Methods for the preparation of this optically-pure intermediate are well known, e.g., Julian et al., J. Am. Chem. Soc., 57, 563-566 (1935) ("Julian et al. I"); Julian et al., J. Am. Chem. Soc., 57, 755-757 (1935) ("Julian et al. II"); Kobayashi, Liebigs Ann. Chem., 536, 143 et seq. (1935); and Dale et al., J. Pharm. Pharmacol., 22, 889-896 (1970). These methods comprise a synthesis in which 1,3-dimethoxy-5-ethoxy oxindole (III) ##STR5## is 3-cyanoalkylated using chloroacetonitrile, with the resulting nitrile (IV) ##STR6## being reduced to a racemic mixture of the amine (V) ##STR7## The racemic mixture is subsequently separated into its enantiomers by a chemical process. This chemical process requires that the racemic amine mixture be successively treated with camphorsulfonic acid and tartaric acid. Each acid functions to crystallize one of the enantiomers (the tartaric acid crystallizing the desirable (3aS) enantiomer), thereby providing for their separation. After separation, the desired (3aS) enantiomer is then cyclized using a reducing agent comprising sodium and ethanol.
Others have modified the foregoing method of cyanoalkylation so that the racemic amine mixture contains the (3aS) enantiomer in excess (about 73%). Lee et al., J. Org. Chem., 56, 872-875 (1991) ("Lee et al. I"). The separation of this enantiomer from the racemic amine mixture, however, was also accomplished by treating the mixture with tartaric acid. Pallavicini et al., Tetrahedron: Asymmetry, 5, 111 et. seq. (1994).
While the foregoing separations of the (3aS) enantiomer using chemical methods, e.g., crystallization using tartaric acid, are operable, there are certain drawbacks to the use of such methods. One of these is the relatively low yields obtainable thereby, this being due to the several steps that are required to be executed to effect such separation. These methods may also employ the use of caustic chemicals.
Another separation method used to effect the separation of racemates which attempts to overcome the drawbacks associated with the aforesaid chemical separation methods involves the use of a separation column. These columns typically include a material therein, referred to as a stationary phase, which functions to cause each enantiomer of a racemic mixture to move through the column at a different rate. Thus, upon operation, when a mobile phase is passed through a column in which the racemic mixture in transiently entrained, one of the enantiomers will elute more rapidly than the other. This allows one to obtain optically-pure solutions of enantiomers by collecting the eluant at different times. This type of one-step separation process is not only easier to complete as compared to the aforementioned multi-step chemical separation processes, but also provides a relatively greater yield of the desired enantiomer.
Articles which relate to the analytical separation of certain physostigmine intermediates into their respective enantiomers using such a column include Lee et al. I and Lee et al., J. Chromatography, 523, 317-320 (1990) ("Lee et al. II"). Lee et al. II describes the use of relatively expensive columns (Chiracel OD/OJ) which contain a benzoylor carbamate-derivatized cellulose-coated stationary phase in the analysis of racemic mixtures, e.g., of (3aS) and (3aR) enantiomers of 1,3-dimethyl-3-cyanomethyl-5-methoxyoxindole (VI) ##STR8## using isopropanol-hexane (10:90) as the mobile phase, wherein the (3aR) enantiomer is the first to elute out of the column.
The work reported in Lee et al. II provides an assay for the intermediates, as opposed to providing a preparative separation method. Moreover, the process disclosed in this article appears to be relatively unpredictable, and highly compound-specific, in that the carbamate (--CH.sub.2 --CH.sub.2 --NH--COOCH.sub.3) and dinitrobenzoyl (--CH.sub.2 --CH.sub.2 --NH--CO--3,5--(NO.sub.2).sub.2 --Ph) amide intermediates disclosed therein are said to be separable in the column, but, surprisingly, the acetamide (--CH.sub.2 --CH.sub.2 --NH--COCH.sub.3) and benzoylamide (--CH2--CH2--NH--CO--Ph) intermediates were not found to be separable thereby. Lee et al. I also discloses an analytical method directed to the assay of the optical purity of the cyanomethyl and the aminoethyl physostigmine intermediates, and of esermethole, using the aforementioned Chiracel columns.
Once one has obtained a physostigmine intermediate, e.g., 1,3-dimethyl-3-cyanomethyl-5-methoxyoxindole (VI), in optically-pure form, by any known process, its efficient conversion into the closed-ring structure of physostigmine and derivatives thereof is of great interest.
Several methods for effecting the conversion of the intermediate into the desired closed-ring structure have been used. One of these methods, disclosed in Julian et al. I and II, and U.S. Pat. No. 4,791,107 to Hamer et al., uses a two-step procedure for the preparation of the physostigmine closed-ring structure starting from (3aS) 1,3-dimethyl-3-cyanomethyl-5-ethoxyoxindole (IV). In the first step, the cyanomethyl group is reduced by palladium/hydrogen to the aminoethyl group, which is then reduced in the second step by sodium in ethanol to obtain the closed-ring structure. In the case of this starting material, a further step, i.e, methylation of the closed-ring thus formed, or alternatively methylation of the aminoethyl group, is required to obtain (3aS) physostigmine.
A second method, set forth in Yu et al., Heterocycles, 36 (6), 1279-1285 (1993); Yu et al., Heterocycles, 27 (7), 1709-1712 (1988); and Lee et al. II, comprises a one-step method for effecting the aforesaid cyclization. This method provides for the reduction of the cyanomethyl derivative in a single step using the reducing agent lithium aluminum hydride. This reducing agent, however, is very hazardous due its extreme flammability.
Therefore, a need exists for a relatively high efficiency, low cost, separation process which is able to separate racemic mixtures of a relatively wider variety of physostigmine intermediates and derivatives thereof as compared to existing separation methods. Of course, a process which operates more quickly than existing processes, and which is able to provide for such separation on a preparative (as opposed to analytic) scale, would also be of great interest.
A further need exists for a safe and efficient method of effecting cyclization of physostigmine intermediates and derivatives thereof.
These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.